This invention relates to fertility control in mammals. In particular, it provides novel, unit dosage, pharmaceutical compositions for reducing blood levels of progesterone.
Orally administered contraceptive medication is now widely practiced in humans, utilizing synthetic progestational and estrogenic substances to produce the same effects as the corresponding natural hormones.
At the beginning of the reporductive cycle in mammals, follicle stimulating hormone (FSH) and luteinizing hormone (LH) are secreted from the pituitary gland and stimulate growth of the ovarian follicles containing the ova. As the follicles grow and develop, estrogen hormones (principally estradiol) are secreted from the follicles in increasing amounts. In the human cycle, high blood levels of estradiol, somewhere around day 12 - 16 of the cycle, stimulate a large secretion of LH which produces ovulation. At this point in time, the woman's basal body temperature (BBT) falls to its lowest point during the cycle. After ovulation (expulsion of ovum from ovary into oviduct), the follicle cavity undergoes cellular changes and is transformed into a body called a corpus luteum. This corpus luteum principally secretes another ovarian hormone, progesterone. This hormone, together with earlier stimulation by estrogen, prepares the lining of the uterus (endometrium) for acceptance of the fertilized ovum (implantation) if the woman has become pregnant. These same hormones "feed back" to inhibit FSH and LH secretion if the woman is pregnant, and no further ovulation occurs until pregnancy has been completed. This biological principle has been applied through use of oral contraceptives; "the pill" contains synthetic estrogens and progestational compounds which act to inhibit FSH and LH and prevent ovulation.
The known methods of ovulation control or prevention have usually involved the oral administration of combined progestational and estrogenic substances at some stage of the cycle. The earlier method, known as combined treatment, involved administering a combination of progestational and estrogenic substances usually on the 5th day after the beginning of the menstrual period, and prior to ovulation, for a period of about 21 days, followed by a cessation until the next cycle. An alternative method, the sequential treatment, only the estrogenic substance is administered for about 16 days, and then a combination dosage for about 5 or 6 days, followed by cessation until the resumption of the cycle.
The use of estrogens in ovulation control is regarded as questionable by some in the medical profession, because of side effects in a small percentage of women.
There have been attempts to control fertility employing only progestational substances, without estrogens, in which the progestational agents were administered continuously throughout the cycle. This resulted in excessive bleeding and irregular menses and possibly some toxic effects due to continuous exposure.
Another way conception can be blocked is by inhibiting or reducing the secretion of progesterone from the corpus luteum after ovulation so that implantation will not occur or, in the event that it occurs, the endometrium cannot support development of the fertilized ovum.
Intensive research has been aimed toward the development of safe, self-administered methods and compositions for terminating human pregnancies during the first trimester. Prostaglandin and its analogues or other related compounds are known to induce menses and abortion; however, the proportion of complete first trimester abortions by this procedure is not sufficiently high to permit such treatment, except as an adjunct to suction currettage. Termination of second trimester pregnancies usually requires a more closely-supervised method to assure safety and effectiveness. Prior art methods include intra-uterine injection of hypertonic saline solution and intra-amniotic injection of prostaglandin. A study of chromosome breakage in peripheral lymphocytes of women on oral contraceptives indicates a small but statistically significant increase in chromosomal breakage among oral contraceptive users. Chromosomal aberrations may increase among offspring of women who conceived while using oral contraceptive therapy.
Prostaglandin and similar compounds have potential utility as luteolytic agents (chemicals which reduce the function of the corpus luteum), uterine stimulants, or menses inducers for use as once-a-month pills. Natural and synthetic prostaglandins have been demonstrated to have luteolytic activity in other mammals but not in humans. However, the presently available prostaglandins have a number of side effects which impose a limitation on their utility in fertility regulation.
Progesterone is often referred to as the hormone of pregnancy because its action on the uterus is required for the maintenance of pregnancy in the human as well as in other mammalian species. There are very specific uterine responses to progesterone hormone stimulation in the mammal and the role of this steroid is becoming better understood with regard to fertility control.
When progesterone enters the cell, it is bound to the cytoplasmic receptor and subsequently to the nuclear receptor. Selective binding of progestational drugs to receptors in the uterus is now indicated. The biological properties of progesterone provide a similar role in most mammals in the reproductive system. Accordingly, the use of active compositions for controlling plasma progesterone with minimum side effects is an important goal of contraceptive research and development.
The use of naturally occurring materials for medicinal purposes has drawn attention to numerous plants as sources for pharmacologically active products. In the fields and mountains of Mexico grow several species of zoapatle. Various species of the zoapatle genus are reputed to have stomachic, diuretic and pectoral properties. Zoapatle species can also provide uterine contractions and can be used as an aid in childbirth by oral administration of an infusion of leaves. In "Contributions From the National Herbarium," Smithsonian Institution, Vol. 23, Part 5, pp. 1529-37 P. C. Standley describes the Montanoa genus among the trees and shrubs of Mexico. Various references cite the species Montanoa tomentosa, which may be taken orally by humans as a decoction of the leaves at the time of delivery to facilitate labor in childbirth and to prevent subsequent exhaustion. The naturally occurring starting product may be harvested at any time of the year, although the relative strength of active constituents may vary seasonally or with climatic or soil conditions.